The overall goal of this research program is the invention and development of novel peptide mimics as isosteric replacements for the structural and functional matrix of biologically active oligopeptides. Toward this end, we will employ a combination of synthetic organic chemistry, molecular modeling, structural studies (NMR and X-ray) of enzyme-inhibitor complexes, and structure activity relationships. Our efforts will be focused upon the design of novel surrogates such as 1,2,3-trisubstituted cyclopropanes that add structural rigidity to the peptide backbone while restricting the conformational space available to the amino acid side chains. A valuable feature of substituting a 1,2,3-trisubstituted cyclopropane for a dipeptide subunit is that this surrogate locks the geometry of the backbone chain in a beta-strand while simultaneously enforcing specific orientation of the amino acid side chain. This mimic should enhance binding of the pseudopeptide by reducing the loss of entropy that occurs upon binding. The general applicability of 1,2,3-trisubstituted cyclopropanes and other new peptide mimics will be established by their incorporation as subunits in inhibitory ligands directed against the aspartate proteases renin and HIV-1 pol-protease, although we anticipate that discoveries made during these efforts may be extended to other areas of peptide mimetics. Cleavage of angiotensinogen by renin is the rate determining step in an enzymic cascade that releases the potent pressor octapeptide angiotensin II. HIV-1 pol-protease is critical for viral replication and formation of mature HIV- 1 particles from infected cells. That 1,2,3-trisubstituted cyclopropanes may be effectively employed as isosteric dipeptide replacements has been convincingly established by preliminary experiments in our laboratories with the design and preparation of renin inhibitors bearing such replacements at the P3 site with subnanomolar IC50's. Future investigations will entail syntheses of pseudopeptides that incorporate 1,2,3-trisubstituted cyclopropanes as dipeptide surrogates at the P1, P2, and P3 sites of potential renin inhibitors and at sites spanning the P2 - P2' consensus sequence of potential inhibitors of HIV-1 pol-protease. During the course of these investigations, general methods for the asymmetric synthesis of 1,2,3-trisubstituted cyclopropanes will be invented and developed. Biological evaluation of potential renin and HIV-protease inhibitors will be performed at Abbott Laboratories. We anticipate that novel drug candidates for the treatment of hypertension and AIDS will emerge from these investigations. We also anticipate that these studies will improve our understanding of the structural, conformational, and dynamic features that underlie receptor-ligand binding and consequent biological properties of peptide ligands.